Context. Alport syndrome (AS) is a hereditary chronic kidney disease (CKD) with X-linked, autosomal and digenic patterns of transmission. Sieving dysfunction of the glomerular basement membrane caused by congenitally defective type IV collagen results in persistent proteinuria, hematuria and progressive renal dysfunction. There are no disease-specific medications and treatment is based on conservative interventions in particular with renin-angiotensin-aldosterone system inhibitors. Subject of Review. Evidence that AS is accompanied by glomerular and tubular inflammatory changes and that bardoxolone methyl exerts anti-inflammatory effects through suppression of NF-kB and activation of transcription of antioxidant and anti-inflammatory genes, provided a justification for the CARDINAL study, a prospective, randomized controlled trial testing the potential renoprotective effect of bardoxolone methyl in 157 adolescent or adult patients with AS. The Authors concluded that bardoxolone methyl preserved estimated glomerular filtration rate (eGFR) relative to placebo at 48 and 100 weeks after randomization. However, exactly the same number of patients (n=3) in each group developed kidney failure. Second opinion. Despite alarming safety signals from previous trials in type 2 diabetics with CKD (increased hospitalizations for heart failure, and fatal and non-fatal cardiovascular events, liver toxicity, and increased blood pressure and albuminuria), major marketing interests encouraged the drug manufacturer to pursue this line of research. Finding that type IV collagen gene mutations account for nearly one third of cases of hereditary glomerulopathies implies that the population of potential target patients could probably be much larger than estimated. Moreover, any new medication approved for AS might receive orphan drug designation which might be associated with shortened time to approval, monetary benefits and a period of market exclusivity. In actual facts, CARDINAL failed to demonstrate any nephro-protective effect of bardoxolone methyl and found an increase in liver enzymes in 70 of the 77 (90.9%) bardoxolone-treated patients consistent with chronic liver toxicity. Indeed, in Zucker diabetic fatty rats treated with an analog of bardoxolone methyl, elevations of liver aminotransferases were associated with enhanced liver weight, severe and diffuse hepatocyte vacuolization, swelling, and degeneration. Moreover, bardoxolone-induced increase in eGFR was associated with a concomitant increase in geometric mean urinary albumin/creatinine ratio, a finding consistent with worsening glomerular hyperfiltration. Considering also the consequent increase in the biomechanical strain on the fragile Alport glomerular basement membrane, this hemodynamic effect is expected to translate into accelerated renal disease progression (consistently with evidence than a bardoxolone methyl analog worsened proteinuria, glomerulosclerosis and tubular damage in Zucker diabetic fatty rats). These concerns induced the Food and Drug Administration to reject the new drug application for bardoxolone methyl submitted by Reata Pharmaceuticals, Inc. with the proposed indication to slow CKD progression in AS patients 12 years of age and older. Thus, bardoxolone methyl is devoid of any nephro-protective effect and is associated with significant heart, liver and renal toxicity in patients with CKD, including those with AS. Because of these safety signals, it should not be used in this clinical context. Research programs could explore the potential clinical applications, even outside the kidney field, of novel NF erythroid 2-like 2 (Nrf2) modulators devoid of bardoxolone methyl toxicity.

S. Karger AG, Basel